Acetic Acid → 8-Bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene

HRID 2044532Notes

Reaction equation

HRID 2044532 reaction equation
[CH:1]([N:4]([C:11]([C:13]1[N:22]=[C:21]2[N:15]([CH2:16][CH2:17][O:18][C:19]3[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:20]=32)[CH:14]=1)=O)[NH:5][C:6](=O)[CH2:7][O:8][CH3:9])([CH3:3])[CH3:2].C(O)(=O)C.[Cl-].[NH4+:33]>O(Cl)Cl.[P+5]>[Br:27][C:25]1[CH:24]=[CH:23][C:20]2[C:21]3[N:15]([CH2:16][CH2:17][O:18][C:19]=2[CH:26]=1)[CH:14]=[C:13]([C:11]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH2:7][O:8][CH3:9])[N:33]=1)[N:22]=3

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 25517Ammonium Chloride2×HCID 582046368-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid N-isopropyl-N'-(2-methoxy-acetyl)-hydrazide

Product 1

HCID 582043878-Bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneYield 76%

Reagents, catalysts & solvents 1

HCID 178479711HCID 178479711, compoundSolvent

Conditions

Temperature
100 °C

Procedure

8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid N-isopropyl-N′-(2-methoxy-acetyl)-hydrazide (1.00 g, 2.29 mmol) was suspended in phosphorus (V) oxychloride (23 mL) then stirred at 100° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue then azeotroped with toluene (×3) giving a brown solid. To the brown solid was added acetic acid (23 mL) and ammonium chloride (1.76 g, 22.9 mmol), the resultant mixture was stirred at 125° C. for 2.5 h then further ammonium chloride (0.88 g, 11.4 mmol) added, the reaction was stirred at 125° C. for 1 h, then concentrated in vacuo. The resultant residue was treated with water and extracted with DCM (×3). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution then followed by brine then dried (Na2SO4) and concentrated in vacuo. The resultant solid was triturated with diethyl ether to give 8-Bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as a light brown solid (0.73 g, 1.74 mmol, 76%). LCMS RT=4.95 min, [M+H]+=418/420. 1H NMR 400 MHz (DMSO-d6) δ: 8.29 (1H, d, J=8.65 Hz), 7.93 (1H, s), 7.31 (1H, dd, J=8.66, 2.05 Hz), 7.25 (1H, d, J=2.05 Hz), 5.79-5.78 (1H, m), 4.49 (4H, s), 4.33 (2H, s), 3.27 (3H, s), 1.43 (6H, d, J=6.60 Hz)

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. customthe residue then azeotroped with toluene (×3)
  3. customgiving a brown solid
  4. stirringthe reaction was stirred at 125° C. for 1 h
  5. concentrationconcentrated in vacuo
  6. additionThe resultant residue was treated with water
  7. extractionextracted with DCM (×3)
  8. washThe combined organic extracts were washed with saturated aqueous sodium bicarbonate solution
  9. dry with materialthen dried (Na2SO4)
  10. concentrationconcentrated in vacuo
  11. customThe resultant solid was triturated with diethyl ether

Sources & evidence

ORD record
ord-4072eac18f3e4a99955c0232cf9874f5
Source dataset
uspto-grants-2013_11
Patent number
US08586574B2

Reaction notes

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